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The introduction of laparoscopic surgery as a procedure to perform radical prostatectomy needs an objective method to evaluate the suitability of this new surgical procedure. The traditional parameters, including the incidence of positive surgical margins, are useful, but not sufficiently objective. Different authors publish different criteria to define positive surgical margins. In addition, there are some technical problems that may ocur during the processing of the surgical specimen by the pathologist, which can give false positive margins. We have used a computer modeling software in connection to scanned images from serial sections of the whole gland, to determine the percentage of extracapsular tissue that surrounds the prostate glands, removed by both, open retropubic and laparoscopic procedures. This percentage can be considered as an objective parameter which can potentially predict the benefit of surgery in predicting cancer control, as well as the clinical success of the surgical procedure. The correlation with the clinical results in the long term--survival and bioche--mical recurrence--will be useful to validate as a last resort the clinical utility of this parameter in the coming years.We had a total of 32 prostate surgical specimens, 15 from patients who underwent open retropubic prostatectomy and 17 from patients who underwent laparoscopic prostatectomy for this study. After surgery and 24 hours formol fixation, serial cuts were taken at 5 mm thickness intervals to make complete sections ("whole mount") of the prostate. An expert uropathologist reviewed all the surgical sections and drew in each tissue cut the prostatic capsule and tumor contours. The serial images of the whole gland and surrounding prostate tissue were scanned to produce digital images, using a computer software to create a file with capsule information and a file with information on the surrounding fibroadipose tissue (extraprostatic). These procedures allowed the reconstruction of a three dimensional tissue model of the prostatic capsule and the surrounding extraprostatic tissue. Two separate point clouds files were generated, with the purpose of representing capsule and extraprostatic tissue models and software algorithms were used to generate differences in point clouds and thereby quantifying the extracapsular tissue coverage dimension, a parameter that we considered indicative of the adequeacy and feasibility of the surgical procedure.The global percentage of prostate gland surface covered by extracapsular fibroadipose tissue was statistically higher in specimens removed by a laparoscopic procedure when compared to the open retropubic procedure. When a segmental analysis of the gland percentage of coverage was evaluated, it was found this percentage was significantly higher in the apical and inferolateral segments of those glands removed without nerves preservation and in the apical segments of those glands removed with nerves preservation for the laparoscopic prostatectomy.In our series. laparoscopic prostatectomy contributed superior extracapsular tissue coverage than retropubic prostatectomy. Similarly laparoscopic prostatectomy produced a superior tissue coverage in inferolateral and apical regions on those glands removed without nerve preservation and in the apical regions of those glands removed with nerve preservation. Therefore, the surgical suitability of this technique, when compared to the retropubic, seems to be higher

Once laparoscopic radical prostatectomy has been mastered, the step to performing a radical cystectomy is not that far. The challenge is to create the urinary diversion by laparoscopy. In this report we describe our experience with 11 laparoscopic radical cystectomies and intracorporeal construction of a continent urinary diversion (Mainz pouch II) as a treatment option in patients with muscle-invading bladder cancer. All 11 procedures could be performed successfully. A conversion to open surgery was not required in any case. The mean surgery time was 6.7 h. Except for two pouch fistulas we did not observe any intra- or postoperative complications. The functional as well as the oncological results are convincing. Less morbidity and faster recovery are the main advantages of this minimally invasive procedure. In addition, the low levels of blood loss, fluid shifts, and electrolyte loss considerably reduce cardiovascular stress. Radical cystectomy and construction of a continent urinary diversion represent the limit of technically feasible laparoscopy and should be done exclusively in specialized centers.

Brachytherapy with 103palladium (103Pd) is an increasingly administered treatment modality for localized prostate cancer. We compared general and disease specific health related quality of life after 103Pd treatment, radical prostatectomy and external beam radiation therapy given during the same time frame.We performed a retrospective cross-sectional survey study of patients treated at a single community medical center between 1995 and 1999. We mailed 5 validated health related quality of life survey instruments to 269, 142 and 222 men who underwent radical prostatectomy, 103Pd treatment and external beam radiation therapy, respectively, with a response rate of greater than 80% in all groups.General health related quality of life assessed by the SF-36 showed the same scores in patients who underwent prostatectomy and 103Pd treatment. The University of California-Los Angeles Prostate Cancer Index was used to assess bowel, urinary and sexual function/bothersomeness. External beam radiation therapy reported was associated with worse bowel function and greater bowel bothersomeness. Prostatectomy was associated with worse urinary function compared to 103Pd and external beam radiation therapy. Prostatectomy was associated with worse sexual function than 103Pd or external beam radiation therapy, although nerve sparing surgery and erectile aids minimized the difference. American Urological Association symptom scores were initially higher for 103Pd but became equal to those in the other groups in patients treated greater than 12 months from survey time. Disease-free men who underwent prostatectomy and 103Pd brachytherapy were equally confident that cancer would not recur in the future. Satisfaction rates were equivalent and biochemical failure significantly decreased satisfaction in all groups.While general health related quality of life was mostly unaffected by the 3 most common treatments for prostate cancer, there were differences in bowel, urinary and sexual function. This information may aid patients in the decision making process.

We assessed the in vivo efficacy of Flt3-ligand (Flt3-L) treatment in C57BL/6 mice bearing a well-established MHC class I-negative prostate carcinoma TRAMP-C1. Flt3-L immunotherapy was initiated approximately 30 days after tumor inoculation, a time whenor =80% of the mice had palpable TRAMP-C1 tumors. Treatment with Flt3-L at 10 microg/day for 21 consecutive days suppressed TRAMP-C1 tumor growth and induced tumor stabilization (P = 0.0337). Enhanced tumor regression was demonstrated at a higher dose of 30 microg/day (P0.0001). Tumors excised from mice treated with Flt3-L were smaller than carrier-treated controls and contained a more pronounced mixed inflammatory cell infiltrate primarily composed of mphi. In regressor nice, tumors reappeared at the site of injection when Flt3-L therapy was terminated. When the experiment was repeated with MHC class I-positive TRAMP-C1 cells, tumor stabilization and/or regression was again observed after treatment (P0.0001); however, once again, tumors reappeared after the termination of therapy despite an extended treatment schedule (35 days). MHC class I-negative variants were present in tumors isolated from carrier- and Flt3-L-treated mice, and this phenotype could be reversed by IFN-gamma treatment in vitro. Thus, Flt3-L treatment of mice with preexisting transplantable prostate tumors results in tumor regression that is dose-dependent and accompanied by a pronounced mixed-cell inflammatory tumor infiltrate. However, disease relapse was invariably observed after the termination of therapy, which suggests that Flt3-L treatment of advanced MHC- prostate cancers will require adjuvant modalities to achieve a durable response.

An intergroup study (SWOG 8795) comparing two forms of adjunctive therapy (immuno and chemo), bacillus Calmette-Guerin (BCG) and mitomycin C (MMC), furnished preregistration index tumors for 244 patients with superficial, papillary stage Ta/T1 TCC. These were examined by flow cytometry to learn whether DNA ploidy or proliferation (low vs high S-phase fraction (SPF) helped to predict disease recurrence or progression.Cell cycle analysis using commercially available (Multicycle) programs was performed on 249 Ta/T1 bladder cancers. Tumor grade, available for 223 cases, was assigned by a single study pathologist. The SWOG statistical office reviewed follow-up information and other data and performed statistical analysis.Disease recurrence occurred in half the cases studied. The most parsimonious model predictive of recurrence included only treatment arm and tumor grade, with the MMC arm and tumor grade greater than I indicating worse prognosis (p = 0. 014). Neither ploidy nor SPF predicted recurrence-free survival or contributed prognostic information that was additive to tumor grade. Within 5 years of follow-up, disease progression or death from bladder cancer occurred for 29/223 (13%) of patients. The most parsimonious model for progression-free survival included only grade greater than I (p0.001) and high SPF (p = 0.029) (relative risk: tumor grade, 4.3, high SPF, 1.9).Knowledge of tumor proliferation (low versus high SPF) contributes prognostic information about tumor progression that is additive to tumor grade.

Substaging of T1 bladder tumors into T1a and T1b based on invasion of the tumor superficial to and beyond the muscularis mucosa has been assigned prognostic significance. We determined whether outcomes after intravesical bacillus Calmette-Guerin (BCG) differ between stage T1a and T1b subcategories.Retrospective pathological evaluation of the initial transurethral resection specimens of stage T1 bladder tumors was performed by 2 pathologists. Grade 1, 2 or 3 and stage T1a or T1b were assigned to each case. Followup was from the date of transurethral resection to date of death or the last visit. Kaplan-Meier probability and log rank test were used to evaluate recurrence and progression.Substaging was performed in 49 of the 55 patients (89%) with stage T1 disease. Disease was stage T1a in 32 (65%), stage T1b in 17 (35%), grade 3 in 45 (92%) and grade 2 in 4 (8%) cases. Maximum followup was 147 months (median 71) and 28 cases had a minimum of 5 years of followup. Recurrence was noted in 33 cases (67.3%), including 22 stage T1a (69%) and 11 stage T1b (65%), at a median followup of 11.3 and 8.6 months, respectively. Progression to a higher stage of disease was recorded in 12 cases (24.4%), including 7 (22%) stage T1a and 5 (29%) stage T1b, at a median followup of 108 and 120 months, respectively. The difference between T1a and T1b subcategories was not statistically significant in regard to recurrence-free (p = 0.7203) and progression-free (p = 0.574) outcomes.Substaging of T1 tumors did not affect response to BCG in regard to recurrence or progression. Therefore, intravesical BCG is effective for stages T1a and T1b disease.

Benign prostate hyperplasia (BPH), a nonmalignant disease with an increasing rate of occurrence associated with advancing age, requires auxiliary markers to help identify its presence and distinguish its progression from prostate cancer.Hybridoma technology was used to generate an antibody against a BPH antigen, which was subsequently characterized by Western blot analysis, sequence homology, and RT-PCR.A BPH-associated protein, designated P25/26, was identified that showed a strong sequence similarity with superimmunoglobulin family members, overexpressed in BPH, with lower expression observed in both normal and prostate cancer tissues.Further studies appear warranted to assess the role that this and other superimmunoglobulin family members may have in the pathogenesis of BPH, and to determine if these glycoproteins have any clinical utility in the differential diagnosis or therapeutic monitoring of BPH.

We analyze patterns of prostate growth in men diagnosed with benign prostatic hyperplasia (BPH) and treated with placebo during 4 years, and determine which baseline parameters were the strongest predictors of growth.A total of 3,040 men were enrolled in the 4-year randomized, placebo controlled Proscar Long-Term Efficacy and Safety study. Of these men a subgroup of 10% underwent pelvic magnetic resonance imaging prostate volume measurement at baseline and yearly thereafter. Absolute and percent volume changes during 4 years were calculated in the 164 placebo treated men in the subgroup. The ability of age, baseline prostate volume and prostate specific antigen (PSA) to predict prostate growth in placebo treated patients was assessed by multiple linear regression analyses, receiver operator characteristics curves, and evaluations of growth stratified by tertiles of baseline serum PSA and decades of life.In placebo treated patients a steady increase in mean plus or minus standard deviation prostate volume from year to year was noted (2.5+/-6.1, 4.9+/-6.8, 6.4+/-8.5 and 7.2+/-8.8 ml. at years 1, 2, 3 and 4, respectively). Mean volume changes at 4 years ranged from -9 to +30 ml. Mean percent change from baseline ranged from 12.5% to 16.6% for men 50 to 59 years old to those 70 to 79 years old. Baseline serum PSA was a strong predictor of growth with 7.4% to 22.0% change at 4 years from the lowest to highest PSA tertiles. Annualized growth rates from baseline were 0.7 ml. per year for PSA 0.2 to 1.3, 2.1 for PSA 1.4 to 3.2 and 3.3 for PSA 3.3 to 9.9 ng./ml. Multiple linear regression analysis showed that serum PSA was a stronger predictor of prostate growth than age or baseline prostate volume. All but 1 man with baseline serum PSA greater than 2.0 ng./ml. had prostate growth during 4 years, and 32.6% of men with serum PSA less than 2.0 exhibited a decrease in volume.Serum PSA is a stronger predictor of growth of the prostate in placebo treated patients than age or baseline prostate volume. Since prostate volume is a risk factor for acute urinary retention and the need for BPH related surgery, the ability of PSA to predict prostate growth may be an important factor when considering individual treatment options for BPH. Such use of PSA represents a shift in paradigm away from focusing solely on symptoms of BPH toward a more comprehensive approach with consideration of predicting and preventing risk factors of BPH related outcomes.

To develop evidence-based guidelines for (1) prostate re-biopsy after radiation and (2) radiation therapy with rising prostate-specific antigen (PSA) levels after radical prostatectomy in the management of patients with localized prostatic cancer.The American Society of Therapeutic Radiology and Oncology (ASTRO) challenged a multidisciplinary consensus panel to address consensus on specific issues in each of the two topics. Four well-analyzed patient data sets were presented for review and questioning by the panel. The panel sought criteria that would be valid for patients in standard clinical practice as well as for patients enrolled in clinical trials. Subsequent to an executive session that followed these presentations, the panel presented its consensus guidelines.Based on the data presented, the prostate re-biopsy negative rates ranged from 62% to 80% for patients with stage T1-2 tumors. The panel judged that prostate re-biopsy is not necessary as standard follow-up care and that the absence of a rising PSA level after radiation therapy is the most rigorous end point of total tumor eradication. Further, the panel judged that re-biopsy may be an important research tool. Based on the data presented, the long-term (5 years or more) PSA remission rate after salvage radiation therapy ranges from 27% to 45%. The panel requested results from prospective randomized trials to evaluate optimally this information. The panel judged that the total dose of radiation should be 64 Gy or slightly higher and that, in patients with or without radiation therapy, there is no standard role for androgen suppressant therapy for rising PSA values after prostatectomy.

Black race has been associated with a significantly increased risk of prostate cancer mortality. This exploratory analysis investigated the effect of race on the clinical outcome of combined androgen blockade (CAB).Data for analysis were obtained from a double-blind, randomized, multicenter trial comparing CAB in the form of bicalutamide (50 mg once daily) or flutamide (250 mg three times daily) plus luteinizing hormone-releasing hormone analogs (LHRHa; goserelin acetate 3.6 mg, or leuprolide acetate 7.5 mg) in 813 patients with stage D(2) prostate cancer (median follow-up, 160 weeks). Patients were analyzed according to race (African American [AA], white, or other). The primary clinical events were disease progression and survival.Four hundred and four patients received bicalutamide/LHRHa and 409 received flutamide/LHRHa. Although treatment with bicalutamide/LHRHa resulted in slightly longer time to progression and survival time in white and AA males than treatment with flutamide/LHRHa, the differences between the treatment groups were not statistically significant.No marked effect of race on clinical outcome was observed regardless of antiandrogen, suggesting that similar treatment benefits are to be expected in either race.

To determine the endocrine effects, efficacy and tolerability of a 10.8-mg depot formulation of Zoladextrade mark (goserelin acetate, Zeneca Pharmaceuticals, Wilmington, Delaware, USA), a luteinizing hormone-releasing hormone agonist analogue, when administration was extended from every 12 weeks to every 13 weeks in patients with advanced prostate cancer.Between July 1995 and May 1996, 59 patients with either locally advanced (T3 or T4) or metastatic prostate cancer were enrolled in an open-label, multicentre trial. Primary efficacy endpoints were testosterone measurements, and assessments of prostate specific antigen (PSA) response, subjective and objective response. Quality of life (QoL) was a secondary efficacy endpoint.Mean testosterone concentrations decreased to0.3 microgram/L by week 4 and remained so for the duration of treatment. There were no statistically significant differences in mean testosterone levels between weeks 12 and 13, or weeks 25 and 26. Serum testosterone suppression was adequate in all 58 evaluable patients at week 13, and 51 of 52 (98%) patients at week 26. Of the 58 evaluable patients, 52 (90%) had a PSA response. A subjective response was recorded for six of 11 evaluable patients. Of 58 patients evaluable for objective response, 46 (79%) had a partial response, three (5%) had stable disease and nine (16%) had objective progression. Except for a significant (P=0.014) decrease in overall sexual interest, QoL was unchanged during therapy. The most common side-effects, regardless of causality, were hot flushes (67%), pain (31%) and pelvic pain (22%). Mild injection-site complaints occurred with only three of 221 (1.4%) depot injections.Zoladextrade mark 10.8-mg depot, administered every 13 weeks to patients with advanced prostatic cancer, is well tolerated, provides adequate suppression of serum testosterone and produces PSA, subjective and objective responses.

Finasteride, a common agent used to treat benign prostatic hyperplasia (BPH), inhibits 5-alpha-reductase. Testosterone is converted by 5-alpha-reductase to the more potent dihydrotestosterone, which is the primary androgen in the prostate. Leuprolide is a stronger antiandrogen that is used to downstage prostate cancer before radical prostatectomy. Leuprolide induces marked atrophy of prostate carcinoma cells, which sometimes makes pathologic diagnosis of cancer difficult, although evaluation at radical prostatectomy is easier than at biopsy. It is unknown whether finasteride produces similar changes, which would result in greater diagnostic difficulty because such changes would be seen on biopsy to rule out cancer in men with suspicious clinical findings treated for BPH. The current study investigated the histologic effects of finasteride therapy on human prostate cancer and benign prostatic tissue on needle biopsy.In blinded manner, we reviewed 53 needle biopsy specimens showing prostate carcinoma (35 treated with finasteride, 18 with placebo). Also reviewed in blinded manner were 50 benign needle biopsy specimens (25 treated with finasteride, 25 with placebo). The Gleason score, number of cores involved, percentage cancer involvement in a core, percentage of atrophic changes in cancer cells, presence of mitoses, blue-tinged mucinous secretions, prominent nucleoli, and high-grade prostatic intraepithelial neoplasia were documented for each case in the cancer group. The percentage of atrophy, basal cell hyperplasia, transitional metaplasia, chronic inflammation, and stromal proliferation was documented for each case in the benign group.No significant histologic differences were present in either the benign or cancer group between cases treated with finasteride and placebo.We conclude that finasteride treatment for BPH does not cause difficulty in the diagnosis of cancer in prostate needle specimens. It is possible that there are severely atrophic areas resulting from finasteride treatment that are undersampled. However, the conclusion that cancer seen on needle biopsy in men treated with finasteride is unaltered and readily identified as cancer remains valid.

Autocrine growth factors for the epidermal growth factor receptor (EGFR) have been identified in prostate tumors, implicating a role for EGFR in the progression of prostate cancer. To investigate early signaling mechanisms used by the EGFR in prostate tumor cells, we have characterized the involvement of the Shc (src homology 2/x-collagen related) adapter protein in EGFR signaling in several human prostate tumor cell lines. In androgen-responsive lymph node-prostate cancer (LNCaP) cells and androgen-insensitive PC3, DU145 and PPC-I cells, Shc was identified as one of the most prominent phosphotyrosine proteins to be elevated in response to EGF. Equivalent levels of the 46- and 52-kDa Shc isoforms were detected in all of the tumor cell lines tested. However, levels of the 66-kDa isoform were variable among the cell lines. In all of the tumor cell lines, EGF caused an association between Shc and Grb2, another adapter protein linked to cellular ras activation. Additionally, several phosphotyrosine proteins, including a 115-120-kDa protein in EGF-treated LNCaP cells, co-associated with Shc. The profile of these Shc-associating proteins, however, differed among the tumor cell lines. Our results indicate that Shc is a common downstream element of EGFR signaling in prostate tumor cells and suggest multiple functions for Shc in prostate tumorigenesis.

In 1997, we believe that either surgery, radiation, or hormonal monotherapy are unlikely to be adequate therapy alone for clinical stage T3 prostate cancer and that primary treatment strategies should use combination therapy. Combination therapies have been investigated in an effort to lessen the impact of monotherapy failure, and combination therapy trials have been shown to diminish the incidence of local failure and increase the time to progression. To gauge the role that irradiation or surgical monotherapy may play in clinical stage T3 disease, this article analyzes series that report local and distant disease control.

We determined whether decreases in prostate specific antigen (PSA) would occur after withdrawal of double-blinded antiandrogen therapy with flutamide or bicalutamide for clinical progression or increasing PSA concentration in patients receiving combined androgen blockade for advanced prostate cancer.PSA concentrations were determined weekly for at least 6 weeks and then every other week for 6 weeks in 22 patients with stage D2 prostate cancer. All patients were withdrawn from antiandrogen therapy (8 flutamide and 14 bicalutamide) due to progression or an increasing PSA concentration. Objective response was evaluated before antiandrogen withdrawal and at week 12.In 4 of 8 patients (50%) withdrawn from flutamide and 4 of 14 (29%) withdrawn from bicalutamide serum PSA concentrations decreased by 50% or more. PSA responses after withdrawal of flutamide therapy occurred within the first few days, whereas those after withdrawal of bicalutamide therapy occurred within 4 to 8 weeks. Of 4 patients assessed for objective response 2 had stable disease and 2 had progression. A PSA response was observed in the 2 patients with stable disease but not the 2 with progression.For patients with stage D2 prostate cancer and disease progression or an increasing PSA concentration, withdrawal of antiandrogen therapy with bicalutamide or flutamide may result in a PSA response. The time to PSA response is longer with bicalutamide than with flutamide. The clinical significance of the antiandrogen withdrawal phenomenon is unknown.

After external beam radiation therapy, pretreatment prostate-specific antigen (PSA) is the most powerful predictor of outcome as measured PSA (biochemical) failure. The post-treatment nadir levels of PSA that predict best for subsequent freedom from PSA failure are debatable, and many nadir levels have been proposed as targets. Although lower nadirs generally are associated with superior outcomes, the identification of a single absolute nadir level was not selected at a recent ASTRO consensus conference. Rather, three consecutive PSA rises above the nadir, with date of failure at the midpoint between the nadir and first rise, were selected as a more useful end point for treatment failure.

Cellular calcium is an important second messenger for growth regulation. We sought to identify potentially important receptors on prostate tumor cells by screening over 20 agonists for their ability to increase intracellular free calcium ([Ca2+]i) in several human prostate tumor cell lines.Intracellular calcium mobilization was detected using fura-2.We found bombesin, GRP, ATP/UTP, lysophosphatidic acid, thrombin, endothelin, histamine, and bradykinin increased [Ca2+]i in the advanced tumor cell lines DU-145, PC3, and PPC-1. Bombesin failed to elevate [Ca2+]i in an immortalized human prostate cell line. Rank-order of potency studies suggested the presence of P2U nucleotide receptors for ATP/UTP on prostate epithelial cells. Potency studies also revealed GRPbombesinneuromedin B at elevating [Ca2+]i in responding tumor cells.These findings indicate that androgen independent prostate tumor cell lines express multiple receptors capable of elevating intracellular calcium, and suggest that GRP receptors may be selectively expressed and/or coupled to calcium signaling during prostate tumor progression. Calcium sensitive cellular events may therefore contribute to the progression of prostate cancer.

We investigated the disease-specific and metastasis-free survival rates in men with locally advanced (clinical stage T3) prostate cancer who were treated surgically.A retrospective, multi-institutional pooled analysis of the results of surgical treatment in 345 men with clinical stage T3 disease was performed. Survival curves were generated using the Kaplan-Meier method.Among 298 evaluable patients, pelvic lymphadenectomy alone was performed in 56 men (19%), while 242 men (81%) underwent node dissection and radical prostatectomy. In total, 122 of 298 patients (41%) had nodal metastases and/or seminal vesicle tumor spread. Pathologically organ-confined disease was noted in 27 men (9%). The actuarial 10-year disease-specific and metastasis-free survival rates for all patients managed surgically were 57 and 32%, respectively. For patients with well, moderately and poorly differentiated tumors, cancer-specific survival rates at 10 years were 73, 67 and 29%, respectively.A large number of men with clinical stage T3 prostate cancer have advanced disease and are unlikely to achieve improved long-term survival with surgery alone. Although there may be a role for radical prostatectomy in selected patients with low to intermediate grade tumors, such treatment appears unlikely to result in long-term survival in men with high grade disease. A prospective study is necessary to determine the optimal treatment approach in men with locally advanced prostate cancer.

Aberrant cellular signaling is a central feature of malignant cells and a potential target for anti-cancer therapy. Carboxyamido-triazole (CAI) is a calcium influx inhibitor that alters calcium-sensitive signal transduction pathways and suppresses the proliferative and metastatic potential of malignant cells. We have examined the effects of CAI on several tumor-associated parameters in human prostate cancer cell lines to evaluate the potential of CAI as a signal-transduction therapy agent for advanced-stage prostate cancer. Measuring anchorage-dependent cell growth, continuous application of CAI inhibited the growth of DU-145, PPC-1, PC3 and LNCaP tumor cells with 50% inhibitory concentrations ranging 10-30 microM. Direct cell enumeration assays revealed that the growth-suppressing activity of CAI toward DU-145 cells was reversible, indicating a cytostatic effect of the drug on tumor cells. The drug also inhibited the proliferation of several immortalized human prostatic epithelial cell lines. The proliferation of HaCaT- and RHEK-1-immortalized keratinocyte cell lines was relatively insensitive to CAI. Additionally, invasion by DU-145, PC3 and PPC-1 cells through Matrigel in vitro was reduced approximately 60-70% by 10 microM CAI. Other cellular effects of CAI included an attenuation of the elevation of intracellular free calcium in response to bombesin and carbachol in PC3 cells and a marked dose-dependent inhibition of prostate-specific antigen secretion in LNCaP cell cultures.

To assess the results of radical prostatectomy in men with early prostate cancer.Retrospective, nonrandomized, multi-institutional pooled analysis.Eight university medical centers in the United States and Europe.A total of 2758 men with stage Tl and T2 prostatic cancer.Disease-specific and metastasis-free survival rates.Tumor grade was the most important preoperative factor in determining outcome. Disease-specific survival 10 years following surgery and associated 95% confidence intervals were 94% (range, 87%-98%), 80% (range, 74%-85%), and 77% (range, 65%-86%) for those men with grade 1, 2, and 3 tumors, respectively. Metastasis-free survival at 10 years was 87% (range, 78%-92%), 68% (range, 62%-73%), and 52% (range, 38%-64%) for patients with grade 1, 2, and 3 cancers, respectively.Radical prostatectomy leads to high 10-year disease-specific survival rates in men with all tumor grades. However, caution is needed in comparing these results with similar studies of alternative treatment strategies, such as watchful waiting, due to the inherent potential biases in uncontrolled trials. Nevertheless, these results offer the best currently available estimates of 10-year outcome of radical prostatectomy in men with clinically localized prostate cancer and may be useful in counseling patients with early malignancy.

To compare the efficacy and safety of goserelin and orchiectomy in patients with stage D2 prostate cancer.A randomized, open, multicenter study was conducted in 283 patients. Patients were allocated to goserelin, 3.6 mg every 28 days or to orchiectomy. Study end points were endocrine response, objective response, time to treatment failure, survival, and tolerability. Objective response was based on modified criteria of the National Prostate Cancer Project.Serum testosterone decreased from baseline to castrate levels by week 4 in each group and remained below castrate levels thereafter. Acid phosphatase and alkaline phosphatase concentrations also decreased in each group. The goserelin and orchiectomy groups had similar results for objective response (82% versus 77%) and had similar medial times to treatment failure (52 versus 53 weeks) and survival (119 versus 136 weeks). No significant interactions between treatments and prognostic factors were observed. Adjusting for baseline testosterone concentration had no effect on survival outcome. Race had no influence on outcome or efficacy end points. Common adverse events in both groups were pain, hot flushes, and lower urinary tract symptoms.Goserelin is well tolerated and as effective as orchiectomy in patients with Stage D2 prostate cancer.

Lung metastases are rarely a significant factor in the management of prostate cancer. The usual pattern of spread is via lymphatic pathways, with pulmonary metastases virtually always occurring with osseous metastases. Previous reports suggest that androgen deprivation often fails to produce significant improvement in patients with pulmonary metastases; however, in the authors' experience, it has been successful in achieving objective responses.A retrospective review of a large prostate cancer data base was performed to identify patients with adenocarcinoma of the prostate and radiographic evidence of pulmonary metastases. A unique case of isolated pulmonary metastases with exsanguinating hemoptysis is described to illustrate the dramatic response to androgen deprivation.Of 1290 patients with biopsy-proven adenocarcinoma of the prostate, in 47 (3.6%) patients radiologic evidence of pulmonary metastases was observed. Twenty-six (2.0%) patients demonstrated pulmonary metastases at the time of initial detection of metastatic disease. The radiographic appearance of pulmonary metastases was consistent with lymphangitic spread in the majority of patients. Of patients who received no hormonal therapy before the development of pulmonary metastases, 76.5% showed improvement in the appearance of their pulmonary lesions with androgen deprivation. As expected, survival was longer for those patients presenting with hormone-naive disease and pulmonary metastases than for patients with hormone-refractory disease and pulmonary metastases. The difference in survival, however, was not statistically significant.Pulmonary metastases are not encountered commonly in patients with prostate cancer. Androgen deprivation remains the most effective treatment and, among hormone-naive patients, objective response is common. The prognosis for patients with hormone-naive disease and pulmonary metastases is not necessarily worse than for patients with metastatic disease at other sites.

Carcinoma in sitii (CIS) of the bladder, which was first described by Melicow in 1952, is the precursor of invasive cancer and may coexist with noninvasive papillary cancer. ’ A spectrum of biological aggressiveness exists for cases of CIS. There may be a long primary in situ phase or a rapid course with a neoplasm becoming invasive after a short in situ phase.? A form fruste lesion of CIS that may represent biologically innocuous epithelium composed of cells having the cytomorphologic features of malignant epithelium without progression has been proposed. The former conferences for consensus development in clinical bladder cancer research recommend that the term transitional CIS is limited to flat lesions with enough cellular anaplasia to be recognized as Such lesions should be graded as grade 2 or grade 3 . The majority will be classified as grade 3 . The entity of CIS in morphological terms should be defined as precisely as possible. The morphologic definition of CIS may be arbitrary but nevertheless critical as a starting point for future discussion.’ Histologically there is anaplasia, disarrangement and/or loss of cellular polarity. The lesion is morphologically flat on cystoscopic examination. Based on the content of the first and second working party reports CIS is therefore defined and classified as follows.2,4

In the case of prostate carcinoma, radiation therapy is a locally applied treatment modality in a malignancy known for systemic dissemination. Because significant efforts and resources currently are being consumed to improve local tumor control, failure patterns and potential curative gain deserve appropriate assessment.From 1975-1989, 647 patients with clinically localized prostate carcinoma were definitively irradiated for biopsy-proven adenocarcinoma of the prostate. Failure patterns were examined, and survival advantage based on improvement in either local or distant disease control was calculated. Distant metastatic rate and cause-specific survival analyses were used as parameters by which to compare the outcome for patients in whom local tumor control was achieved with patients who experienced local failure, thereby assessing further the importance of the effectiveness of locally applied therapy.Three hundred ninety-two (61%) patients at the time of this writing were clinically disease free. Sixty-two (10%) patients failed locally only, 133 (20%) distantly only, and 60 (9%) developed local and distant recurrent disease. Both local and distant failure rates were higher in patients with more advanced stage lesions at presentation, and distant failure rates significantly increased in patients with less differentiated tumors. Pretreatment prostate-specific antigen was found to be useful in predicting recurrence patterns. Overall, there appeared to be more potential for improvement in survival secondary to reducing distant metastasis. The distant survival advantage (DSA) of reducing distant metastases, compared with the local survival advantage (LSA) of improving local tumor control, was 26 versus 14%. Although DSA was greater than LSA within each stage category, the potential to improve survival was most significant in the Stage C group, where DSA was 35% and LSA 16%. Although LSA varied little according to tumor grade, DSA was dependent on tumor grade and varied from 13% for well differentiated lesions to 38% for poorly differentiated lesions. Distant failure free survival at 10 years was 63% for patients with local control and 45% for those with local failure (P = 0.01). Similarly, 10-year cause-specific survival was 75% in locally controlled patients compared with 48% for those with local recurrence (P0.001).Although better local tumor control should translate into at least modest survival gain for patients with prostate carcinoma, additional advantage may be seen with improved systemic therapy or perhaps earlier diagnosis to reduce further the distant metastasis rate.

Three new potential biomarkers--PAC, PMA, and the 7E11-C5 glycoprotein--have been identified. All three have unique features that could augment current diagnostic and therapeutic modalities. Some of the important characteristics of these potential markers are summarized in Table 1. Further studies will be required to determine if any of them will provide clinical information beyond that provided by PSA and if they will have a significant impact on the management of patients with prostate cancer. The MAb 7E11-C5 (CYT-356), now in clinical trials, promises to offer new strategies for radioimmunodetection and radioimmunotherapy of prostate cancer.

Prognostic factors have been shown to be important when stratifying patients with prostate cancer into randomized trials and counseling the individual patient regarding his chances of response to treatment. However, there are no reports on prognostic factors in patients with Stage D2 prostate cancer treated with a pure antiandrogen as monotherapy.The authors studied a variety of possible prognostic factors among 150 patients with metastatic prostate cancer treated with an antiandrogen (Casodex, Imperial Chemical Industries, Wilmington, DE).In a univariate analysis, performance status; extent of disease (EOD); pretreatment hemoglobin, alkaline phosphatase, prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP) levels; and extent of disease (EOD) on bone scan all were found to be significant prognostic factors (P0.05). Pretreatment serum testosterone levels, identified as one of the most important prognostic factors, was not identified as significant in the current study.Although the pretreatment testosterone level was shown to be an important prognostic factor in previous studies, using other modes of androgen ablation (reducing testosterone to below castrate levels), the current study suggest it may not be a helpful factor if the therapy used is antiandrogens as monotherapy. This may relate to the different mode of action of antiandrogens, which do not reduce serum testosterone levels.

Over the last 2 decades, the prognostic significance of post-irradiation prostate biopsy has been debated. Studies with long-term follow-up have shown a predictive effect with regard to local tumor failure and disease-free survival. More recently collected data involve the use of prostate ultrasound and prostate-specific antigen; the latter appears to be a good prognostic indicator on its own. Currently, the practical usefulness of post-treatment biopsy for clinically undetectable disease remains undefined, since definitive therapy for positive findings cannot be widely applied, carries significant morbidity, and, as yet, is of questionable benefit. Further study is certainly necessary, and it is perhaps under these conditions that this post-therapy procedure should be used.

Bladder washing specimens containing inflammatory or squamous cells have been difficult to accurately analyze with single-parameter DNA flow cytometric (FCM) methods.The anticytokeratin 18 antibody, CK5, was used in a multiparameter assay of 275 bladder washing and voided urine specimens to immunoselect only the bladder transitional cells for DNA analysis.Flow cytometric detection of transitional cell carcinoma was increased by immunoselection of CK5-positive cells in specimens from patients with disease. Unfortunately, a similar increase in hyperdiploid cells in pathologically benign specimens was observed, which resulted in a false-positive rate of 45%. In some instances, multiparameter FCM assays with CK5 could detect aneuploid cell populations not clearly evident by single-parameter analysis.However, the results from this study of the hyperdiploid cell fraction showed that the increased sensitivity resulting from the use of CK5 was not clinically useful because of the decrease in specificity.

We developed a double-determinant immunoradiometric assay for measuring serum prostate secretory protein (PSP), using monoclonal antibodies (MAb) against two different epitopes: MAb PSP-19 was the capture antibody and MAb PSP-6 was the tracer antibody. Assay sensitivity was 0.1 microgram/L. Analytical recovery of PSP was 93.5-104.6%, whereas the intra- and interassay mean CVs were 4.2% and 6.9%, respectively. In 92 normal men, ages greater than 50 years, the mean PSP concentration was 5.7 micrograms/L, with 10 (10.9%) men having concentrations greater than 10 micrograms/L. In contrast, 20 of 49 (40.8%) patients with benign prostate hyperplasia (BPH; mean PSP concentration 9.4 micrograms/L) and 46 of 100 (46%) patients with prostate cancer (mean PSP concentration 22.2 micrograms/L) had PSP concentrations greater than 10 micrograms/L. Mean serum PSP concentrations of the BPH (P less than 0.05) and prostate cancer (P less than 0.01) groups were significantly different from those of age-matched normal men. In a small group of patients, serial PSP concentrations correlated with the clinical course during therapy. Thus, PSP may be a useful marker for evaluating patients with prostate cancer.

Premalignant lesions of the penis include cutaneous horn, balanitis xerotica obliterans, and leukoplakia. The true incidence of progression of each of these to squamous-cell carcinoma is unknown. Bowenoid papulosis, erythroplasia of Queyrat, and Bowen's disease are histologically identical to in situ carcinoma. Although the first is consistently benign, the latter two regularly evolve into invasive cancer. Malignant scrotal lesions include squamous-cell carcinoma, liposarcoma, leiomyosarcoma, basal-cell carcinoma, extramammary Paget's disease, erythroplasia of Queyrat, malignant melanoma, and metastases. Hemangioma can be confused with carcinoma.

The incidence of local failure and its relation to distant failure following definitive therapy of carcinoma of the prostate is discussed. Local failure may arise from incomplete resection, tumor spillage, clones of radioresistant cells, development of new tumors in an organ left in situ, or inadequate treatment portals. The authors review the various measures used as prophylaxis or treatment of local failure in relation to clinical and pathologic stage.

A monoclonal antibody (MAb) designated PD41 (IgG1k) was generated by hyperimmunizing BALB/c mice with a membrane preparation prepared from a moderately to poorly differentiated prostate carcinoma surgical specimen. The immunohistochemical reactivity of MAb PD41 was shown to be highly restricted to the ductal epithelia and secretions of prostate adenocarcinoma tissues. Sixty-five % of the prostate tumor specimens were stained with MAb PD41, whereas no staining of the fetal or benign prostate specimens was observed. PD41 reacted minimally with normal prostate tissues, with less than 1% of the epithelial cells staining. This MAb did not react with nonprostate carcinomas or to a variety of normal human tissues. Using both radioimmunoassay and immunofluorescent procedures, several cultured human tumor cell lines, human blood cells, and purified antigens to prostate-specific antigen and prostatic acid phosphatase also were found not to express the PD41 antigen. MAb PD41 also was shown to bind to the target antigen present in seminal plasma obtained from prostate carcinoma patients but not to seminal plasma from normal donors. Immunoblots of gel-separated components of prostate carcinoma tissue extracts indicate that the molecular weight of the proteins carrying the PD41 antigenic determinant can differ among individual tumors, ranging from Mr 90,000 to greater than 400,000. However, in seminal plasma from prostate cancer patients, the predominant component recognized by PD41 is the diffuse Mr greater than 400,000 band. It appears that this monoclonal antibody may recognize a prostate carcinoma-associated mucin-like antigen, which is preferentially expressed on prostate carcinomas, and therefore, may be a useful marker to distinguish benign prostate hyperplasia from prostate carcinoma.

In summary, hemibody irradiation has developed as a safe, efficient technique for palliating multiple sites of symptomatic osseous metastases, which occur so often in advanced prostatic carcinoma. The rapidity, frequency, and duration of pain relief, as well as the convenience to the patient of a solitary treatment to multiple symptomatic areas simultaneously, make this type of treatment especially appealing. By following premedication and radiation dose guidelines, both acute and delayed side effects can be kept tolerable or at a minimal incidence. Although sequential hemibody radiation has also been explored as "systemic" therapy, the results in prostatic carcinoma have not proved dramatic, and complications have been considerable. Hormonal therapy would certainly seem to be less life-threatening and equally beneficial according to present data. As a palliative treatment, however, hemibody irradiation is a pragmatic option for relieving prostatic cancer pain.

We report preliminary results for the first 164 patients enrolled in a multicenter study comparing the endocrine effects, efficacy, and safety of 3.6 mg of goserelin acetate (Zoladex) and orchiectomy in patients with Stage D2 prostate cancer. Eighty-one patients were randomly allocated to receive Zoladex and 83 to orchiectomy. The median follow-up time for all patients was two hundred ten days. Median serum levels of testosterone were reduced to castrate levels (less than 50 ng/dL) within four weeks in both groups and remained suppressed for up to sixty weeks. An objective response according to modified criteria of the National Prostatic Cancer Project was observed in 81 percent and 78 percent of patients in the Zoladex and orchiectomy groups, respectively. There were no statistically significant differences between treatment groups in the distributions of time to treatment failure or time to disease progression. The most commonly reported adverse events in both treatment groups were hot flashes, cancer-related pain, unspecified pain, and urinary symptoms. These results suggest that Zoladex may offer an alternative to orchiectomy in the treatment of advanced prostate cancer.

The topic of treatment of complications that occur after interstitial therapy for stage A2 adenocarcinoma of the prostate is somewhat unique. While a number of series have studied complications after radiation therapy based on field size, dose delivered, dose fractions, and anatomic and physiologic characteristics of the host, rarely have they categorized complications of therapy based on pretreatment clinical stage. This I seek to do here on the basis of my experience with interstitial implantation with the 125I isotope in 126 patients at Eastern Virginia Medical School, Norfolk, Virginia (USA). Complications after interstitial therapy are divided into a) acute, those that occur within the first 3 months, and b) chronic, those that persist beyond 3 months or occur at some interval greater than 3 months after therapy.

The authors review their institution's experience with the failure of definitive treatment to achieve local tumor control and with the distant dissemination and local morbidity associated with such failure. The causes of local failure are various: incomplete resection, implantation of spilled cells, and, possibly, selective implantation of circulating tumor cells in traumatized tissues after surgery and totally or partially resistant cells, new tumors, or radiologic misses after radiation. Treatment of local failure may be prophylactic or therapeutic and differs depending on the stage of the disease. Failure to control the tumor locally in the presence of distant metastases does not alter the length of survival, but it can profoundly affect the quality of survival.

Of 169 patients with a minimum of 4 years follow-up treated definitively with irradiation for adenocarcinoma of the prostate, 100 had transurethral prostatic resection (TURP) before treatment. In comparing that group with the group who did not have TURP, osseous metastases developed in 28% versus 22%, respectively. Further stratification by tumor grade and stage failed to show TURP-dependent tumor dissemination, whereas the incidence of bony metastasis increased progressively with decreasing tumor differentiation and advancing tumor stage.

Fifty patients with testicular carcinoma, 45 with prostatic neoplasm, 84 with bladder carcinoma, and 13 with benign bladder papilloma were evaluated for skin reactivity to DNCB and other intradermal antigens. Correlation between pathologic staging and skin-test reactivity was sought. Reaction to DNCB among patients with testis tumors was more significantly depressed by chemotherapy than by the extent of retroperitoneal or distant metastatic disease indicating that skin testing as a means of following the course of disease or of predicting survival may be limited by alterations caused by chemotherapy. DNCB reactivity did not correlate with the prognosis for the different stages of disease, but follow-up studies of individual patient survival are needed for substantiation. Depression of DNCB reactivity exists among patients with prostatic carcinoma whether the disease is localized or widely metastatic. Only lengthy follow-up will determine if there is any correlation of reactivity with survival in individual patients. DNCB reactivity among patients with bladder tumors shows progressive reduction with increasing stage disease and lends support to the evidence suggesting immune deficiency in patients with bladder neoplasm.

We evaluated and compared five commercial radioimmunoassay kits with a standard counter-immunoelectrophoretic assay for the measurement of prostatic acid phosphatase in serum. Four of the five radioimmunoassays performed as described by the supplier with respect to sensitivity, stability, precision, linearity, analytical recovery, and expected values for the normal male population. None of the radioimmunoassays was more clinically sensitive then the counter-immunoelectrophoretic assay for detecting increased prostatic acid phosphatase in serum. Results obtained by counter-immunoelectrophoretic assay agreed with results obtained by radioimmunoassay in 96% of the tests. The proportion of positive results in patients with confirmed prostatic adenocarcinoma increased with disease progression. The fewer positive tests in localized adenocarcinoma (Stages A and B) suggests that neither the counter-immunoelectrophoretic assay nor the radioimmunoassay procedures are useful for screening unselected populations for adenocarcinoma of the prostate. The high percentage of normal values found in those patients clinically free of disease after treatment is encouraging and supports the use of the prostatic acid phosphatase immunoassays in prospectively monitoring the treatment of prostatic cancer patients.